Catalytic aza-Nazarov cyclization reactions to access α-methylene-γ-lactam heterocycles

We have developed a catalytic aza-Nazarov reaction of N-acyliminium salts generated in situ from the reaction of a variety of cyclic and acyclic imines with α,β-unsaturated acyl chlorides to afford substituted α-methylene-γ-lactam heterocycles. The reactions proceed effectively in the presence of catalytic (20 mol %) amounts of AgOTf as an anion exchange agent or hydrogen-bond donors such as squaramides and thioureas as anion-binding organocatalysts. The aza-Nazarov cyclization of 3,4-dihydroisoquinolines with α,β-unsaturated acyl chlorides gives tricyclic lactam products 7 in up to 79% yield with full diastereocontrol (dr = >99:1). The use of acyclic imines in a similar catalytic aza-Nazarov reaction with 20 mol % of AgOTf results in the formation of α-methylene-γ-lactam heterocycles 19 in up to 76% yield and with good to high diastereoselectivities (4.3:1 to 16:1). We have demonstrated the scalability of the reaction with a gram-scale example. The relative stereochemistry of the α-methylene-γ-lactam products 19 has been determined via the single-crystal X-ray analysis of lactam 19l. In order to shed light on the details of the reaction mechanism, we have performed carefully designed mechanistic studies which consist of experiments on the effect of β-silicon stabilization, the alkene geometry of the α,β-unsaturated acyl chloride reactants, and adventitious water on the success of the catalytic aza-Nazarov reaction.


1
H NMR spectra and at 77.16 ppm for 13 C{ 1 H} NMR spectra). 1  Materials: Anhydrous CH3CN was obtained by distillation over P2O5 under an inert atmosphere of nitrogen. Anhydrous CH2Cl2 and DME were purchased from Acros Organics (AcroSeal®) and used as received. Silver trifluoromethanesulfonate (AgOTf) (99+%) was purchased from Acros Organics, and stored in a desiccator. All other commercially available reagents were used as received unless stated otherwise.
3,4-Dihydroisoquinoline derivatives 5a and 5b were prepared following literature procedures. 1 The syntheses of the aza-Nazarov products 19b, 19c, and 19f were described in our initial Gram-scale synthesis of acyl chloride 6b: Compound 15 was prepared following a procedure reported in the literature. 2 To a solution of triethyl phosphonoacetate (14, 4.00 g, 3.57 mL, 18.7 mmol) in DME (8.0 mL) was added NaH (749 mg, 18.7 mmol, 60% dispersion in mineral oil) as a solid at 0 °C under an inert atmosphere of nitrogen. After the reaction mixture was stirred at 23 °C for 30 min, TMSCH2I (4.59 g, 3.18 mL, 21.4 mmol) was added. The resulting mixture was stirred at 70 °C for 125 min, and the progress of the reaction was monitored by TLC. The reaction mixture was then cooled to ambient temperature and quenched with a saturated aqueous solution of NH4Cl.
The aqueous phase was extracted three times with CHCl3. The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
This reaction was repeated twice, and the crude mixtures were combined. S4 Purification by flash column chromatography (EtOAc/hexanes 1:1) gave pure product 15 as a colorless oil (6.997 g, 60% yield).
The spectral data match those reported in the literature. 1 A solution of 17 (2.489 g, 11.6 mmol) in 10.0 mL of (COCl)2 (oxalyl chloride) was heated at 60 °C for 2 h. It was then cooled to ambient temperature, and removal of excess (COCl)2 using a rotary evaporator inside a well-ventilated fume hood gave 6b as an orange oil (2.571 g, 95% yield, E:Z = 3:1).
The spectral data match those reported in the literature. 1 Note: This product is sensitive to water. Therefore, it was used immediately after preparation. h. It was then cooled to ambient temperature and quenched with a saturated aqueous solution of NaHCO3 (10 mL). The aqueous phase was extracted with CH2Cl2 (3  15 mL). The combined organic phase was dried over Na2SO4, filtered, and concentrated under reduced pressure.
After stirring the reaction mixture for 1 h, the reaction was quenched with 10% aqueous S20 ammonia solution (10 mL) solution and brine (10 mL). The aqueous phase was extracted with EtOAc (3  30 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography twice: first attempt (EtOAc/hexanes 1:2, Rf = 0.38) gave a colorless oil.

X-ray diffraction analysis of aza-Nazarov product 19l:
A suitable crystal of compound 19l was selected for data collection which was performed on a Bruker diffractometer equipped with a graphite-monochromatic MoKα radiation at 296 K. We used these procedures for our analysis: solved by direct methods; SHELXS-2013; 9 refined by full-matrix least-squares methods; SHELXL-2013; 10 data collection: Bruker APEX2; 11 molecular graphics: MERCURY; 12 solution: WinGX. 13 Details of data collection and crystal structure determinations are given in Table S3.  Figure S1: The molecular structure of 19l, showing 50% probability displacement ellipsoids and the atomic numbering.       (Z)